J Mahlangu1, P Paz2, M Hardtke3, F Aswad2, J Schroeder3. 1. Haemophilia Comprehensive Care Centre, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa. 2. Global Biologics Research, Lead Discovery, Bayer, San Francisco, CA, USA. 3. Global Clinical Development, Bayer Pharma AG, Berlin, Germany.
Abstract
INTRODUCTION: The most serious and challenging complication of haemophilia treatment is development of inhibitors to replacement factors VIII or IX. Innovative therapies currently being explored for patients with haemophilia and inhibitors include BAY 86-6150, a modified recombinant activated factor VII (FVIIa). Immunogenicity remains a substantial barrier in this endeavour. AIM: To present safety and efficacy results of the BAY 86-6150 study in patients with inhibitors and report detailed analysis of epitope mapping in a patient who developed anti-BAY 86-6150 antibodies. METHODS: Patients aged 12-62 years with moderate or severe haemophilia A or B were eligible for the phase 3 TRUST trial if they had a history of high-titre inhibitors. Four escalating doses of BAY 86-6150 (6.5, 20, 50, 90 μg kg-1 ) were planned with ≥10 patients per dose level. Bleeding episodes were treated with BAY 86-6150. Development of anti-BAY 86-6150 antibodies was considered a serious adverse event. RESULTS: TRUST was discontinued after one patient in the 6.5-μg kg-1 cohort developed anti-BAY 86-6150 neutralizing antibodies following three exposures. The anti-BAY 86-6150 antibodies cross-reacted with and neutralized wild-type FVIIa (WT-FVIIa). Post hoc epitope mapping using peripheral blood mononuclear cells from the responding patient found that none of the 14 peptides unique to BAY 86-6150 were recognized by the patient's T cells, but strong responses were detected against 2 WT-FVIIa peptides. CONCLUSION: In the single patient with haemophilia A who developed anti-BAY 86-6150 antibodies, results of T-cell epitope mapping indicated BAY 86-6150 was no more immunogenic than WT-FVIIa.
INTRODUCTION: The most serious and challenging complication of haemophilia treatment is development of inhibitors to replacement factors VIII or IX. Innovative therapies currently being explored for patients with haemophilia and inhibitors include BAY 86-6150, a modified recombinant activated factor VII (FVIIa). Immunogenicity remains a substantial barrier in this endeavour. AIM: To present safety and efficacy results of the BAY 86-6150 study in patients with inhibitors and report detailed analysis of epitope mapping in a patient who developed anti-BAY 86-6150 antibodies. METHODS:Patients aged 12-62 years with moderate or severe haemophilia A or B were eligible for the phase 3 TRUST trial if they had a history of high-titre inhibitors. Four escalating doses of BAY 86-6150 (6.5, 20, 50, 90 μg kg-1 ) were planned with ≥10 patients per dose level. Bleeding episodes were treated with BAY 86-6150. Development of anti-BAY 86-6150 antibodies was considered a serious adverse event. RESULTS: TRUST was discontinued after one patient in the 6.5-μg kg-1 cohort developed anti-BAY 86-6150 neutralizing antibodies following three exposures. The anti-BAY 86-6150 antibodies cross-reacted with and neutralized wild-type FVIIa (WT-FVIIa). Post hoc epitope mapping using peripheral blood mononuclear cells from the responding patient found that none of the 14 peptides unique to BAY 86-6150 were recognized by the patient's T cells, but strong responses were detected against 2 WT-FVIIa peptides. CONCLUSION: In the single patient with haemophilia A who developed anti-BAY 86-6150 antibodies, results of T-cell epitope mapping indicated BAY 86-6150 was no more immunogenic than WT-FVIIa.
Authors: Wojciech Jankowski; Joseph McGill; H A Daniel Lagassé; Stepan Surov; Gary Bembridge; Campbell Bunce; Edward Cloake; Mark H Fogg; Katarzyna I Jankowska; Abdul Khan; Joseph Marcotrigiano; Mikhail V Ovanesov; Zuben E Sauna Journal: Blood Adv Date: 2019-09-10
Authors: Johnny Mahlangu; Howard Levy; Marina V Kosinova; Heghine Khachatryan; Bartosz Korczowski; Levani Makhaldiani; Genadi Iosava; Martin Lee; Frank Del Greco Journal: Res Pract Thromb Haemost Date: 2021-08-17
Authors: Miguel Escobar; Giancarlo Castaman; Santiago Bonanad Boix; Michael Callaghan; Philippe de Moerloose; Jonathan Ducore; Cédric Hermans; Janna Journeycake; Cindy Leissinger; James Luck; Johnny Mahlangu; Wolfgang Miesbach; Ismail Haroon Mitha; Claude Négrier; Doris Quon; Michael Recht; Jean François Schved; Amy D Shapiro; Robert Sidonio; Alok Srivastava; Oleksandra Stasyshyn; Kateryna V Vilchevska; Michael Wang; Guy Young; W Allan Alexander; Ahmad Al-Sabbagh; Daniel Bonzo; Christopher Macie; Thomas A Wilkinson; Craig Kessler Journal: Haemophilia Date: 2021-10-11 Impact factor: 4.263